Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents

Nabissi, Massimo; Morelli, Maria Beatrice; Santoni, Matteo; Santoni, Giorgio

doi:10.1093/carcin/bgs328

Cited by 202 publications

(194 citation statements)

References 41 publications

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“…Here, similar results were obtained where CBD activated TRPV2 at concentrations ≥ 10 μM, although a complete concentration-response relationship was not. Subsequently, TRPV2-mediated effects of CBD upon the chemosensitivity of a glioblastoma multiforme cell line to conventional cytotoxic agents were reported [100]. Interestingly, in addition to activating TRPV2, CBD also stimulated TRPV2 expression in this cell line.…”

Section: Trp Channelsmentioning

confidence: 91%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

425

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Trp Channelsmentioning

confidence: 91%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

425

323

View full text Add to dashboard Cite

show abstract

“…By contrast, TRPV2 is highly expressed in normal, but not in neoplastic (glioblastoma), brain tissue (Morelli et al, 2012). Overexpression of TRPV2 inhibits glioblastoma growth in a mouse xenograft model and promotes differentiation toward a more mature glial phenotype (Morelli et al, 2012;Nabissi et al, 2013). In other words, TRPV2 may function as an oncogene in the prostate and a tumor suppressor gene in the brain.…”

Section: G Transient Receptor Potential Channels In Cancermentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…Several recent studies have also suggested the potential of TRP channels as pharmacologic targets for cancer treatment. The coadministration of cannabidiol, a TRPV2 agonist, potentiated the activity of cytotoxic drugs temozolomide, carmustine, or doxorubicin, and increased drug uptake in human GBM cells (Nabissi et al, 2013). Interestingly, in malignant human gliomas, the chronic application of the TRPC inhibitor SKF 96365 (1-[2-[4-methoxy-3-[3-(4-methoxyphenyl)propoxy]phenyl]ethyl]imidazole) caused near total growth arrest (Bomben and Sontheimer, 2008).…”

Section: Calcium Channel-associated Transientmentioning

confidence: 99%

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

Morrone¹,

Gehring²,

Nicoletti³

2016

Mol Pharmacol

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Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calciumpermeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca 21 activity plays an important role in the regulation of cell proliferation, and Ca 21 signaling is altered in proliferating tumor cells. A series of previous studies emphasized the importance of the T-type low-voltage-gated calcium channels (VGCC) in different cancer types, including gliomas, and remarkably, pharmacologic inhibition of T-type VGCC caused antiproliferative effects and triggered apoptosis of human glioma cells. Other calcium permeable channels, such as transient receptor potential (TRP) channels, contribute to changes in Ca 21 by modulating the driving force for Ca 21 entry, and some TRP channels are required for proliferation and migration in gliomas. Furthermore, recent evidence shows that TRP channels contribute to the progression and survival of the glioblastoma patients. Likewise, the purinergic P2X7 receptor acts as a direct conduit for Ca 21 -influx and an indirect activator of voltage-gated Ca 21 -channel. Evidence also shows that P2X7 receptor activation is linked to elevated expression of inflammation promoting factors, tumor cell migration, an increase in intracellular mobilization of Ca 21 , and membrane depolarization in gliomas. Therefore, this review summarizes the recent findings on calcium channels and associated receptors as potential targets to treat malignant gliomas.

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Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents

Cited by 202 publications

References 41 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

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